In vitro induction of human immunodeficiency virus type 1 variants resistant to 2'-beta-Fluoro-2',3'-dideoxyadenosine

Antimicrob Agents Chemother. 1997 Jun;41(6):1313-8. doi: 10.1128/AAC.41.6.1313.


2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA) is an acid-stable purine dideoxynucleoside analog active against a wide spectrum of human immunodeficiency virus type 1 (HIV-1) and HIV-2 strains in vitro. F-ddA is presently undergoing a phase I clinical trial at the National Cancer Institute. We induced HIV-1 variants resistant to F-ddA by exposing wild-type HIV-1 (HIV-1LAI) to increasing concentrations of F-ddA in vitro. After 18 passages, the virus was fourfold less sensitive to F-ddA than HIV-1LAI. Sequence analyses of the passage 18 virus revealed changes in three amino acids in the reverse transcriptase (RT)-encoding region of the pol gene: P to S at codon 119 (P119S; present in 3 of 13 and 28 of 28 molecular clones before and after F-ddA exposure, respectively), V179D (0 of 13 and 9 of 28, respectively), and L214F (9 of 13 and 28 of 28, respectively). Drug sensitivity assays using recombinant infectious clones confirmed that P119S was directly responsible for the reduced sensitivity of HIV-1 to F-ddA. Various infectious clones with single or multiple amino acid substitutions conferring viral resistance against nucleoside RT inhibitors, including HIV-1 variants with multi-dideoxynucleoside resistance, were generally sensitive to F-ddA. The moderate level of resistance of HIV-1 to F-ddA, together with the lack of conferment of significant cross-resistance by the F-ddA-associated amino acid substitutions, warrants further investigation of F-ddA as a potential antiviral agent for use in treatment of HIV-1 infection.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-HIV Agents / pharmacology*
  • COS Cells
  • Deoxyadenine Nucleotides / pharmacology
  • Dideoxyadenosine / analogs & derivatives*
  • Dideoxyadenosine / pharmacology
  • Dideoxynucleotides
  • Drug Resistance, Microbial
  • Genes, pol
  • HIV Reverse Transcriptase / drug effects
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / genetics*
  • Humans
  • Microbial Sensitivity Tests
  • Mutation
  • Reverse Transcriptase Inhibitors / pharmacology
  • Thymine Nucleotides / pharmacology
  • Zidovudine / analogs & derivatives
  • Zidovudine / pharmacology


  • Anti-HIV Agents
  • Deoxyadenine Nucleotides
  • Dideoxynucleotides
  • Reverse Transcriptase Inhibitors
  • Thymine Nucleotides
  • 2',3'-dideoxyadenosine triphosphate
  • lodenosine
  • Zidovudine
  • Dideoxyadenosine
  • zidovudine triphosphate
  • HIV Reverse Transcriptase